This invention relates to sustained release (depot) formulations of drugs in particular voter soluble peptides, e.g. somatostatin or somatostatin analogs, such as octreotide, in a biodegradable and biocompatible polymeric carrier, e.g. a matrix or a coating, e.g. in the form of a implant or preferably a microparticle (also known as a microcapsule or a microsphere).
The invention also relates to such formulations, showing satisfactory peptide release profiles over a particular period of time.
Peptide drugs often show after oral or parenteral administration a poor bioavailability in the blood, e.g. due to their short biological half-lives caused by their metabolic instability. If orally or nasally administered they additionally often show a poor resorption through the mucuous membranes. A therapeutically relevant blood level over an extended period of time is difficult to achieve.
The parenteral administration of peptide drugs as a depot formulation in a biodegradable polymer, e.g. as microparticles or implants, has been proposed enabling their sustained release after a residence time in the polymer which protects the peptide against enzymatic and hydrolyric influences of the biological media.
Although some parenteral depot formulations of peptide drugs in a polymer in the form of microparticles or an implant, are known, satisfactory peptide release profiles are in practice only obtained in very few cases. Special measures must be taken to achieve a continuous peptide release for a therapeutically active drug serum level and if desired to avoid too high drug serum concentrations, which cause undesired pharmacological side reactions.
The peptide drug release pattern is dependent on numerous factors, e.g. the type of the peptide, and e.g. whether it is present in its free or in another form, e.g. salt form, which may influence its water solubility. Another important factor is the choice of polymer, from the extended list of possibilities which have been described in the literature.
Each polymer type has its characteristic biological degradation rate. Free carboxyl groups may be formed which contribute to the pH value in the polymer and thus additionally influence the water solubility of the peptide and thus its release pattern.
Other factors, which may influence the release pattern of the depot formulation, are the drug loading of its polymeric carrier, the manner of its distribution in the polymer, the particle size and, in case of an implant, additionally its shape. Another factor is the site of influence of the formulation in the body.
Until now no somatostatin composition in sustained release form for parenteral administration has reached the market, perhaps because no composition exhibiting a satisfactory serum level profile could be obtained.